Project Abstract/Summary Despite advances in medical therapy and mechanical revascularization, myocardial infarction (MI) remains a major cause of morbidity and mortality. While acute treatment of MI is associated with low in-hospital mortality, a significant proportion of patients develop recurrent ischemic events during long-term follow-up. Identifying inflammatory mechanisms underlying increased myocardial injury in the peri-MI period may help direct novel therapeutics and more intensive medical therapy focused on the etiology of disease. Recent evidence suggests that a specific monocyte subset (Mon2; CD14++/CD16+) is a major pro-inflammatory mediator of cardiomyocyte injury during MI, but the triggers leading to increased monocyte activation and recruitment are poorly defined. Platelets are also a primary mediator of thrombotic injury: monocyte-platelet aggregates (MPA) are elevated in MI, and the extent of their presence may be associated with the severity of tissue injury. These observations have led to the formulation of the central hypothesis that MPA promote recruitment and activation of pro-inflammatory monocytes during MI, and that appropriate anti-platelet drug therapy can limit myocardial injury and long-term adverse cardiovascular events among patients with elevated levels of MPA and monocyte activation. This project proposes to (1) quantitate the association between circulating monocyte platelet aggregates (MPA) and cardiovascular outcomes after myocardial infarction, as well as the circulating levels of CD14++CD16+ monocytes in myocardial infarction; (2investigate the monocyte subtypes that are activated in MPA, the effect of inhibiting platelet P2Y12 receptors on MPA formation, and the role of monocyte integrin activation in mediating monocyte adhesion; and (3) determine the differential effect of antiplatelet agents on formation of MPA and monocyte activation. To test these hypotheses, peripheral and coronary blood samples will be obtained at the time of cardiac catheterization and percutaneous coronary intervention for treatment of MI. Blood samples will be analyzed by flow cytometry to quantify MPA and monocyte subtypes. An arterial mimetic adhesion assay (A chip) will be used to quantitate monocyte subset adhesion to VCAM-1, and the relative adhesion of monocyte subtypes in MPA. Clinical follow-up will establish a relationship between MPA, monocyte subset activation, and major adverse cardiovascular events. In vitro and clinical analysis of the effect of more intensive platelet inhibition with ticagrelor or prasugrel on MPA will identify future therapeutic strategies for individualized antiplatelet treatment among patients after MI.